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Pediatric Nephrology

, Volume 20, Issue 8, pp 1098–1105 | Cite as

Childhood thin GBM disease: review of 22 children with family studies and long-term follow-up

  • Carla Carasi
  • William G. Van’t Hoff
  • Lesley Rees
  • R. Anthony Risdon
  • Richard S. Trompeter
  • Michael J. Dillon
Original Article

Abstract

Thin glomerular basement membrane (GBM) disease is generally known to have a good renal prognosis, although renal insufficiency has sometimes been reported and the overlap with Alport syndrome implies that a good prognosis cannot be guaranteed. In order to shed light on long-term prognosis of thin GBM disease we have retrospectively evaluated 22 children with persistent haematuria and biopsy-proven thin GBM. Mean follow up was 7 years (range 2–17 years), mean age at onset was 7 years (range 1.5–15). Biopsies were performed a mean of 3.8 years after detection of hematuria. The light microscopy (LM) and immunofluorescence (IF) findings were essentially unremarkable in all of the children, while electron microscopy (EM) showed thinning of the GBM in all cases and no changes characteristic of Alport syndrome. The family history was positive for renal disease in 17 (77.3%) patients with hematuria in 8 (36.3%) families, and hematuria with renal failure (RF) or deafness in 9 (40.9%). It was completely negative for renal disease in 4 (18.2%) and unavailable in 1 (4.5%). Four patients (18%) showed a decline in renal function after 6, 8, 9 and 12 years of follow-up, and 1 of these also developed hearing impairment. None developed hypertension.

Our study suggests that thin GBM disease is not always benign and a child with thin GBM should never be assigned such a prognosis, especially if there is a family history of renal impairment or deafness, where careful follow-up is needed due to the risk of late onset renal failure.

Keywords

Thin glomerular basement membrane disease Familial benign hematuria Alport syndrome 

Notes

Acknowledgements

We acknowledge the support of Dr Frances Flinter, Clinical Director of Children’s Service & Genetics & Consultant Clinical Geneticist at Guy’s & St. Thomas’ Hospital, London, who kindly undertook the genetic analysis. We also acknowledge Professor Graziella Zacchello, Dr. Luisa Murer, Dr. Giovanni Montini (Pediatric Nephrology Consultants), and Dr Lina Artifoni (Consultant Geneticist) from the Department of Pediatrics, Dialysis and Transplant Unit, University of Padova, Italy, for kindly reviewing the manuscript and for their helpful comments. The results of this study were presented in part at the World Congress of Nephrology at Berlin, in 2003.

References

  1. 1.
    Roth KS, Amaker BH, Chan JCM (2001) Pediatric hematuria and thin basement membrane nephropathy: what is it and what does it mean? Clin Pediatr 40:607–613Google Scholar
  2. 2.
    Lang S, Stevenson B, Risdon RA (1990) Thin basement membrane nephropathy as a cause of recurrent haematuria in childhood. Histopathology 16:331–337PubMedGoogle Scholar
  3. 3.
    Piqueras AI, White RH, Raafat F, et al (1998) Renal biopsy diagnosis in children presenting with hematuria. Pediatr Nephrol 12:386–391PubMedGoogle Scholar
  4. 4.
    Yoshikawa N, White RHR, Cameron AH (1982) Familial hematuria: clinical-pathological correlations. Clin Nephrol 17:172–182PubMedGoogle Scholar
  5. 5.
    Kashtan CE (1998) Alport syndrome and thin glomerular basement membrane disease. J Am Soc Nephrol 9:1736–1750PubMedGoogle Scholar
  6. 6.
    Glassock R, Adler SG, Ward HJ, Cohen AH (1991) Primary glomerular diseases. In: Brenner BM, Rector FC (eds) The kidney. WB Saunders, Philadelphia, PA, pp 1182–1279Google Scholar
  7. 7.
    Rogers PW, Kurtzman NA, Bunn SM Jr, et al (1973) Familial benign essential hematuria. Arch Intern Med 131:257–262PubMedGoogle Scholar
  8. 8.
    McLay AL, Jackson R, Meyboom F, Jones JM (1992) Glomerular basement membrane thinning in adults: clinicopathological correlations of a new diagnostic approach. Nephrol Dial Transpl 7:191–199PubMedGoogle Scholar
  9. 9.
    Tiebosch AT, Frederik PM, van Breda Vriesman PJ, Moog JMV, van Rie H, van de Wiel TWM, Wolters J, Zeppenfeldt E (1989) Thin-basement-membrane nephropathy in adults with persistent hematuria. N Engl J Med 320:14–18PubMedGoogle Scholar
  10. 10.
    Aarons I, Smith PS, Davies RA, Woodroffe AJ, Clarkson AR (1989) Thin membrane nephropathy: a clinical-pathological study. Clin Nephrol 32:151–158PubMedGoogle Scholar
  11. 11.
    Abe S, Amagasaki Y, Iyori S, Konishi K, Kato E, Sakaguchi H, Shimoyama K (1987) Thin basement membrane syndrome in adults. J Clin Pathol 40:318–322PubMedGoogle Scholar
  12. 12.
    Saxena S, Davies DJ, Kirsner RLG (1990) Thin basement membranes in minimally abnormal glomeruli. J Clin Pathol 43:32–38PubMedGoogle Scholar
  13. 13.
    Trachtman H, Weiss RA, Bennet B, Greifer I (1984) Isolated hematuria in children: indications for a renal biopsy. Kidney Int 25:94–99PubMedGoogle Scholar
  14. 14.
    Goel S, Davenport A, Goode NP, Shires M, Hall CL, Harrison PR, Maciber AG (1995) Clinical features and outcome of patients with thin and ultrathin glomerular membranes. Q J Med 88:785–793Google Scholar
  15. 15.
    Arneil GC, Lam CN, McDonald M (1969) Recurrent haematuria in 17 children. Br Med J 2:233–5PubMedGoogle Scholar
  16. 16.
    Ayoub EM, Vernier RL (1965) Benign recurrent haematuria. Am J Dis Child 109:217–223PubMedGoogle Scholar
  17. 17.
    Bodian M, Black JA, Kobayashi N, Lake BD, Shuler SE (1965) Recurrent hematuria in childhood. Q J Med 34:359–382PubMedGoogle Scholar
  18. 18.
    Glasgow EF, Moncrieff MW, White RHR (1970) Symptomless haematuria in childhood. Br Med J 2:687–692PubMedGoogle Scholar
  19. 19.
    Pardo V, Brion MG, Levi DF, Strauss J (1979) Benign primary hematuria. Clinicopathology study of 65 patients. Am J Med 67:817–822PubMedGoogle Scholar
  20. 20.
    Schoeneman MJ, Earon Y, Spitzer A, Greifer I (1979) Idiopathic persistent microscopic haematuria in children. Prognostic features. NY State J Med 79:1714–1718Google Scholar
  21. 21.
    Ozen S, Ertoy D, Heidet L, Cohen-Solal L, Ozen H, Besbas N, Bakkaloglu A, Antignac C (2001) Benign familial hematuria associated with a novel COL4A4 mutation. Pediatr Nephrol 16:874–877PubMedGoogle Scholar
  22. 22.
    Rumpelt HJ, Langer KH, Scharer K, Straub E, Thones W (1974) Split and extremely thin glomerular basement membranes in hereditary nephropathy (Alport’s syndrome). Virchows Arch Path Anat Hist 364:225–233Google Scholar
  23. 23.
    Gubler MC, Gonzalez-Burchard G, Monnier C, Habib R (1976) Alport’s syndrome: Natural history and ultrastructural lesions of glomerular and tubular basement membranes. Contr Nephrol 2:163–169Google Scholar
  24. 24.
    Rumpelt HJ (1980) Hereditary nephropathy (Alport syndrome): correlations of clinical data with glomerular basement membrane alterations. Clin Nephrol 13:203–207PubMedGoogle Scholar
  25. 25.
    Dische F, Weston M, Parsons V (1985) Abnormally thin glomerular basement membranes associated with hematuria, proteinuria or renal failure in adults. Am J Nephrol 5:103–109PubMedGoogle Scholar
  26. 26.
    Nieuwhof CMG, de Heer F, de Leeuw P, van Breda Vriesman PJC (1997) Thin GBM nephropathy: premature glomerular obsolescence is associated with hypertension and late onset renal failure. Kidney Int 51:1596–1601PubMedGoogle Scholar
  27. 27.
    Habib R, Gubler MC, Hinglais N, et al (1982) Alport’s syndrome: experience at Hopital Necker. Kidney Int 21:S20–28Google Scholar
  28. 28.
    Piel CF, Biava CG, Goodman JR (1982) Glomerular basement membrane attenuation in familial nephritis and “benign” hematuria. J Pediatr 101:358–365PubMedGoogle Scholar
  29. 29.
    Lemmink HH, Nillesen WN, Mochizuki T, Schröder CH, Brunner HG, van Oost BA, Monnens LAH, Smeets HJM (1996) Benign familial hematuria due to mutation of type IV collagen alpha4gene. J Clin Invest 98:1114–1118PubMedGoogle Scholar
  30. 30.
    Badenas C, Praga M, Tazon B, et al (2002) Mutations in the COL4A4 and COL4A3 genes cause familial benign hematuria. J Am Soc Nephrol 13:1248–1254PubMedGoogle Scholar
  31. 31.
    Gunwar S, Ballester F, Noelken ME, Sado Y, Ninomiya Y, Hudson BG (1998) Glomerular basement membrane. Identification of a novel disulfide-cross-linked network or α3, α4, and α5 chains of type IV collagen and its implications for the pathogenesis of Alport syndrome. J Biol Chem 273:8767–8775Google Scholar
  32. 32.
    Boye E, Mollet G, Forestier L, et al (1998) Determination of the genomic structure of the COL4A4 gene and of novel mutations causing autosomal recessive Alport Syndrome. Am J Hum Genet 63:1329–1340Google Scholar
  33. 33.
    Buzza M, Daghre H, Wang YY, et al (2003) Mutations in the COL4A4 gene in the thin basement membrane disease. Kidney Int 63:447–453PubMedGoogle Scholar
  34. 34.
    Wang YY, Rana K, Tonna S, Lin T, Sin L, Savige J (2004) COL4A3 mutations and their clinical consequences in thin basement membrane nephropathy (TBMN). Kidney Int 65:786–790PubMedGoogle Scholar
  35. 35.
    Van der Loop FTL, Heidet L, Timmer EDJ (2000) Autosomal dominant Alport syndrome caused by a COL4A3 splice site mutation. Kidney Int 58:1870–1875PubMedGoogle Scholar
  36. 36.
    Turco AE, Renieri A, De Marchi M (1997) Alport syndrome: is there a genotype-phenotype relationship? Nephrol Dial Transpl 12:1551–1552Google Scholar
  37. 37.
    Lemmink HH, Mochizuki T, van den Heuvel LPWJ, et al (1994) Mutations in type IV collagen α3 (COL4A3) gene in autosomal recessive Alport syndrome. Hum Mol Genet 3:1269–1273PubMedGoogle Scholar
  38. 38.
    Mochizuki T, Lemmink HH, Mariyama M, et al (1994) Identification of mutations in the α3 (IV) and α4 (IV) collagen genes in autosomal recessive Alport syndrome. Nat Genet 8:77–82PubMedGoogle Scholar
  39. 39.
    Heidet L, Arrondel C, Forestier L, Cohen-Solal L, Mollet G, Gutierrez B, Stavrou C, Gubler MC, Antignac C (2001) Structure of the human type IV collagen gene COL4A3 and mutations in autosomal Alport syndrome. J Am Soc Nephrol 12:97–106PubMedGoogle Scholar
  40. 40.
    Hirose K, Osterby R, Nozawa M, Gundersen HJ (1982) Development of glomerular lesions in experimental long-term diabetes in the rat. Kidney Int 21:889–95Google Scholar
  41. 41.
    Gubler MC, Antignac C, Deschenes G, et al (1993) Genetic, clinical and morphologic heterogeneity in Alport syndrome. Adv Nephrol 22:15–35Google Scholar
  42. 42.
    Collar JE, Ladva S, Cairns TD, Cattell V (2001) Red cell traverse through thin glomerular basement membranes. Kidney Int 59:2069–72PubMedGoogle Scholar
  43. 43.
    Kashtan CE, Michael AF (1996) Alport syndrome. Kidney Int 50:1445–1463PubMedGoogle Scholar
  44. 44.
    Lemmink HH, Kluijtmans LAJ, Brunner HG (1994) Aberrant splicing of the COL4A5 gene in patients with Alport syndrome. Hum Mol Genet 3:317–322PubMedGoogle Scholar
  45. 45.
    Schröder CH, Bontemps CM, Assmann KJM, Schuurmans Stekhoven JH, Foidart JM, Monnens LAH, Veerkamp JH (1990) Renal biopsy and family studies in 65 children with isolated hematuria. Acta Paediatr Scand 79:630–636Google Scholar
  46. 46.
    Van der Loop FTL, Monnens LAH, Schroder CH, et al (1999) Identification of COL4A5 defects in Alport’s syndrome by immunohistochemistry of skin. Kidney Int 55:1217–1224PubMedGoogle Scholar
  47. 47.
    Nakanishi K, Yoshikawa N, Iijima K, et al (1994) Immunohistochemical study of α1–5 chains of type IV collagen in hereditary nephritis. Kidney Int 46:1413–1421PubMedGoogle Scholar
  48. 48.
    Gubler MC, Knebelmann B, Beziau A, et al (1995) Autosomal recessive Alport syndrome: immunohistochemical study of type IV collagen chain distribution. Kidney Int 47:1142–1147PubMedGoogle Scholar

Copyright information

© IPNA 2005

Authors and Affiliations

  • Carla Carasi
    • 3
  • William G. Van’t Hoff
    • 1
  • Lesley Rees
    • 1
  • R. Anthony Risdon
    • 2
  • Richard S. Trompeter
    • 1
  • Michael J. Dillon
    • 1
  1. 1.Department of NephrologyGreat Ormond Street Hospital for Children NHS TrustLondonUK
  2. 2.Department of HistopathologyGreat Ormond Street Hospital for Children NHS TrustUK
  3. 3.Department of Paediatrics, Dialysis and Transplant UnitUniversity of PadovaPadovaItaly

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